Interactions between Neuronal Innate Immune Pattern Recognition Receptor Pathways and Neurotropic Arboviruses: Host Measures, Viral Countermeasures, and Potential Therapeutics.

Neurotropic arboviruses are a group of pathogens capable of causing severe and fatal central nervous system infections for which there are few effective treatments or vaccines. The extent of neurotropic arbovirus-mediated destruction of central nervous system neurons is often an important determinant in the severity and clinical outcome after infection. Early cellular innate immune responses mediated by pattern recognition receptors (PRRs) are often vital for effective pathogen control, and an effective neuronal innate immune response may be crucial to prevent the essentially irreversible loss of critical central nervous system neurons by neurotropic arboviruses. The work presented here describes efforts to preserve neurotropic arbovirus-infected neurons by: a) studying the interactions between neurotropic arboviruses and neuronal PRR pathways in order to indentify novel targets for future therapeutics, and b) identifying potential anti-neurotropic arbovirus medications which target viral replication. Innate PRR pathways function in both a cell and pathogen-specific manner. However, relatively little is known about the induction and regulation of neuronal PRR signaling. Therefore, I assessed PRR pathway expression and function in neurons and found that neurons possess functional PRR pathways mediated by select receptors and signaling molecules which activate the downstream transcription factors NFkB and IRF3 resulting in the production of genes with putative antiviral activity. Next, I characterized how neuronal PRR pathways interact with neurotropic arboviruses using western equine encephalitis virus (WEEV) as a model neurotropic arbovirus. From these studies I concluded that IRF3 mediates a neuron-protective response to WEEV; however, this response was independent of type-I IFN signaling, which possesses potent antiviral activity and is canonically activated downstream of IRF3 in alternate cell types. Importantly, WEEV inhibited neuronal PRR-mediated induction of antiviral type-I interferons, and this inhibitory capacity was mapped to the WEEV capsid protein. These data indicated that neuronal PRR pathways may be important determinants in neurotropic arbovirus pathogenesis and that neuronal PRR pathways and viral countermeasures to them may be exploited to develop anti-neurotropic arboviral treatments. Finally, I identified a novel class of small molecules which inhibit WEEV replication, protect neuronal cells from WEEV-induced cell death, and may be a useful component of future anti-neurotropic arbovirus therapies.Ph.D.Microbiology & ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91521/1/peltierd_1.pd

Nox2 redox signaling maintains essential cell populations in the brain.

Reactive oxygen species (ROS) are conventionally classified as toxic consequences of aerobic life, and the brain is particularly susceptible to ROS-induced oxidative stress and damage owing to its high energy and oxygen demands. NADPH oxidases (Nox) are a widespread source of brain ROS implicated in seizures, stroke and neurodegeneration. A physiological role for ROS generation in normal brain function has not been established, despite the fact that mice and humans lacking functional Nox proteins have cognitive deficits. Using molecular imaging with Peroxyfluor-6 (PF6), a new selective fluorescent indicator for hydrogen peroxide (H(2)O(2)), we show that adult hippocampal stem/progenitor cells (AHPs) generate H(2)O(2) through Nox2 to regulate intracellular growth signaling pathways, which in turn maintains their normal proliferation in vitro and in vivo. Our results challenge the traditional view that brain ROS are solely deleterious by demonstrating that controlled ROS chemistry is needed for maintaining specific cell populations

Deceleration of probe beam by stage bias potential improves resolution of serial block-face scanning electron microscopic images.

Serial block-face scanning electron microscopy (SBEM) is quickly becoming an important imaging tool to explore three-dimensional biological structure across spatial scales. At probe-beam-electron energies of 2.0 keV or lower, the axial resolution should improve, because there is less primary electron penetration into the block face. More specifically, at these lower energies, the interaction volume is much smaller, and therefore, surface detail is more highly resolved. However, the backscattered electron yield for metal contrast agents and the backscattered electron detector sensitivity are both sub-optimal at these lower energies, thus negating the gain in axial resolution. We found that the application of a negative voltage (reversal potential) applied to a modified SBEM stage creates a tunable electric field at the sample. This field can be used to decrease the probe-beam-landing energy and, at the same time, alter the trajectory of the signal to increase the signal collected by the detector. With decelerated low landing-energy electrons, we observed that the probe-beam-electron-penetration depth was reduced to less than 30 nm in epoxy-embedded biological specimens. Concurrently, a large increase in recorded signal occurred due to the re-acceleration of BSEs in the bias field towards the objective pole piece where the detector is located. By tuning the bias field, we were able to manipulate the trajectories of the  primary and secondary electrons, enabling the spatial discrimination of these signals using an advanced ring-type BSE detector configuration or a standard monolithic BSE detector coupled with a blocking aperture

Test in a beam of large-area Micromegas chambers for sampling calorimetry

Application of Micromegas for sampling calorimetry puts specific constraints on the design and performance of this gaseous detector. In particular, uniform and linear response, low noise and stability against high ionisation density deposits are prerequisites to achieving good energy resolution. A Micromegas-based hadronic calorimeter was proposed for an application at a future linear collider experiment and three technologically advanced prototypes of 1$\times$1 m$^{2}$ were constructed. Their merits relative to the above-mentioned criteria are discussed on the basis of measurements performed at the CERN SPS test-beam facility

Arterial cerebral blood volume–weighted functional MRI using pseudocontinuous arterial spin tagging (AVAST)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110725/1/mrm25220.pd

Maturation-dependent responses of human neuronal cells to western equine encephalitis virus infection and type I interferons

AbstractInnate cell-autonomous antiviral responses are essential first lines of defense against central nervous system infections but may also contribute to neuropathogenesis. We investigated the relationships between innate immunity and neuronal differentiation using an in vitro culture system with human cell lines to analyze cellular responses to the neurotropic alphavirus western equine encephalitis virus. Human neuronal cells displayed a maturation-dependent reduction in virus-induced cytopathology that was independent of autocrine interferon α or β activity. In addition, maturation was associated with enhanced responsiveness to exogenous stimuli, such that differentiated neurons required five- to ten-fold less type I interferon to suppress viral replication or virus-induced cytopathology compared to immature cells, although this enhanced responsiveness extended to only a subset of unique type I interferons. These results demonstrate that maturation-dependent changes in human neuronal cells may be key determinants in the innate immune response to infections with neurotropic alphaviruses

The Adaptation Challenges and Strategies of Adolescent Aboriginal Athletes Competing Off Reserve

Within the motivation literature, it has been indicated that athletes respond more effectively to sport’s contextual challenges through effective adaptation skills. Fiske identified five core motives as facilitators of the adaptation process across cultures: belonging, understanding, controlling, self-enhancement, and trusting. Through a cultural sport psychology approach, the adaptation challenges and strategies of Canadian Aboriginal adolescent athletes from one community (Wikwemikong) are described as they traveled off reserve to compete in mainstream sporting events. Concurrently, Fiske’s core motives are considered in relation to youth sport participants from the aforementioned Aboriginal community. Culture sensitive research methods among the Wikwemikong, including community meetings, talking circles (TCs), indigenous coding, and coauthoring, were employed in this article. Data are reflected in three themes: (a) challenges pursuing sport outside of the Aboriginal community in advance of bicultural encounters, (b) challenging bicultural encounters in Canadian mainstream sport contexts, and (c) specific responses to racism and discrimination

Internal convection in thermoelectric generator models

Coupling between heat and electrical currents is at the heart of thermoelectric processes. From a thermal viewpoint this may be seen as an additional thermal flux linked to the appearance of electrical current in a given thermoelectric system. Since this additional flux is associated to the global displacement of charge carriers in the system, it can be qualified as convective in opposition to the conductive part associated with both phonons transport and heat transport by electrons under open circuit condition, as, e.g., in the Wiedemann-Franz relation. In this article we demonstrate that considering the convective part of the thermal flux allows both new insight into the thermoelectric energy conversion and the derivation of the maximum power condition for generators with realistic thermal coupling.Comment: 8 pages, 3 figure

Dispelling the myths of online education: learning via the information superhighway

There continues to be a perception that online education is inferior to traditional education. In the U.S. online learning is more developed than in the U.K. This paper provides insights into a U.S. provision and takes a close look at what are perceived as weaknesses of on line learning and argues that these are not necessarily inherent weaknesses of this form of educational delivery. Then, results of two major studies, undertaken in the U.S. are provided comparing the effectiveness of online education to traditional education as perceived by current MBA students and past graduates. Results of these studies suggest that students of MBA modules and MBA graduates perceive the quality and effectiveness of online education to be similar to, if not higher than, the quality and effectiveness of traditional modules and programmes